Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion

Hum Pathol. 2001 Jul;32(7):734-40. doi: 10.1053/hupa.2001.25586.

Abstract

This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man with human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors.

Publication types

  • Case Reports

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / pathology
  • Adenine / adverse effects*
  • Adenine / analogs & derivatives
  • Adult
  • Antiviral Agents / adverse effects*
  • Cytochrome-c Oxidase Deficiency
  • DNA, Mitochondrial / analysis
  • DNA, Mitochondrial / drug effects*
  • DNA, Mitochondrial / metabolism
  • Dissection
  • Drug Therapy, Combination
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • HIV Infections / drug therapy*
  • HIV Infections / enzymology
  • HIV Infections / pathology
  • Humans
  • Immunoenzyme Techniques
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / ultrastructure
  • Male
  • Micromanipulation
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Necrosis
  • Organophosphonates*
  • Polymerase Chain Reaction
  • Succinate Dehydrogenase / genetics
  • Succinate Dehydrogenase / metabolism

Substances

  • Antiviral Agents
  • DNA, Mitochondrial
  • Organophosphonates
  • adefovir
  • Succinate Dehydrogenase
  • Electron Transport Complex IV
  • Adenine